Dr. Steven Almo, an expert in x-ray crystallography, has spearheaded an exciting collaborative effort in conjunction with Dr. Zhong-Yin Zhang, an enzymologist, and Dr. David Lawrence, a synthetic chemist in order to design potential theraputic agents for and understand the structures of protein tyrosine phosphatases. This effort has been made possible using crystal diffraction data collected at beamline X9B of the Resource. Data collected on rotating anode diffractometers at AECOM have provided data with insufficient resolution to adequately define the strutucre of the enzyme complexed with ligands. Using synchrotron methods, Dr. Almo's group has recently solved the structure of a mutant tyrosine phosphatase complexed with several synthetic non-peptide substrates to better than 2.0 resolution. A structure based on the active site mutant, where a cystine amino acid side chain was replaced with a serine side chain (essentially a substitution of oxygen for sulfur in the structures) was also solved to 3.0 resolution. The inactive mutant is important, because it can be examined in the presence of substrates, since they are not cleaved. Interestingly, and of functional significance, is the fact that the diffraction pattern improved for crystals where substrate is bound, indicating a 'tightening up" of the overall structure. One of these inhibitors was found to possess a second, novel binding mode, which may provide additional information for the design of tight-binding inhibitors specific to the phosphatase. These protein tyrosine phosphatases constitute a class of enzymes whose roles in oncogenesis and signal transduction are of significance; consequently, it will be crucial to understand the structural basis of their specificity to rationally design therapeutic agents to control cell growth and signalling.